MSS: Muscle Structure And Adaptation

Question 1

Describe the cellular origins of skeletal muscle.

Answer 1

The muscle forms from the somites, which are blocks of paraxial mesoderm. This consists of a sphere on columnar epithelial cells surrounding a transient cavity. Under extrinsic signals the somite is divided into 4 major compartments.

Closest to the notochord, we have the SCLEROTOME, which will differentiate into bone, ribs and cartilage. Following that, there is a layer of SYNDETOME cells, which will become tendons. Then, a layer of MYOTOME, which becomes the muscle precursors. Finally, on the outside, we have the DERMOTOME, which becomes the dorsal dermis.

Question 2

Describe myogenesis.

Answer 2

Paracrine factors induce the mesodermal cells with myogenic regulatory factors (MRF), such as Myf5 and MyoD. Once the cells have committed, they are known as myoblasts.

These myoblasts proliferate due to growth factors, and exit the cell cycle. They start to express myogenin (a mrf), which is known as terminal differentiation.

They form myotubes as structural proteins start to be expressed such as myosin and actin. These myotubes align and fuse.

Then comes biphasic muscle development, where we first get a primary form of cells, then a secondary form of cells that are based off the architecture of the first cells. There is also a third group of myoblasts that doesn’t differentiate but sits closely to the muscle fibres. These are known as satellite cells, and are responsible for the regeneration and postnatal growth of muscle cells.

Question 3

What is special about the embryonic fibre number?

Answer 3

In most species, muscle fibre number is determined at birth; thus, it is genetically determined.

However, the fibre number can be affected by:

• temperature
• hormones
• nutrition
• innervation

These can affect the myogenic regulatory factor expression and duration of expression.

Question 4

Describe post-natal growth (hypertrophy).

Answer 4

After birth an increase in muscle mass is due to an increase in fibre size (hypertrophy).

Muscle Stem Cells (MuSCs) contribute to the muscle fibre. They’re called satellite cells; they are undifferentiated muscle precursors, and are self-renewing.

MuSCs proliferate and incorporate into the muscle fibres, where they contribute to the production of structural proteins, which causes an increase in muscle fibre size. They return to the quiescence when not needed - left to be activated at a later stage.

They maintain the cytoplasm:nuclei ratio in the muscle fibre.

Question 5

Muscle Stem Cells maintain the cytoplasm:nuclei ratio in the muscle fibre. The cells are multinucleated.
Why is this important?

Answer 5

This is done to supply the increased production of structural proteins in the growing muscle fibre.

Also, the muscle fibres have a lot of mitochondria, and a lot of the genes needed for mitochondria production is found in the nuclei.

Question 6

Another process used to increase muscle mass is hyperplasia.

Describe postnatal muscle growth: hyperplasia.

Answer 6

Hyperplasia is an increase in muscle mass due to an increase in muscle cell/fibre number. It is debated whether this occurs but there is evidence to support this such as the avian stretch model and cat weight-lifting model.

The proposed mechanisms include the fibre splitting and SC activation. Evidence this happens in humans is lacking but it probably does happen but hypertrophy is the main factor. It is difficult to test hyperplasia in humans due to ethical and technical considerations.

Question 7

Summary of myogenesis

Answer 7

• Myoblasts develop from myogenic precursor cells which are of mesodermal origin
• Myogenic commitment and terminal differentiation regulated by MRF
• Fibre number set at birth, postnatal increase in muscle mass due mostly to hypertrophy (although hyperplasia may also play a role.)

Question 8

How do we get fibre-type diversification?

Answer 8

Even though we have the same proteins between different fibre types, there is a lot of variation between the proteins, which gives the muscle fibres a distinct characterisation.

All the vertebrae’s sarcomere structure is the same. However, we have a high degree of molecular variability in the proteins, depending on the function.
There are multiple isoforms of the myofibrillar proteins that have come about due to alternative splicing, or using different promoters to drive gene expression.

Muscle fibre type composition will adapt over time to the needs of the of the body (training.)

Question 9

Give some examples of myofibrillar protein isoforms, and what differs between them.

Answer 9

MYOSIN isoforms:

• different chemo mechanical transduction
• ATP hydrolysis
• shortening velocity

TROPONIN and TROPOMYOSIN isoforms:
- sensitivity to Ca2+

TITIN isoforms:
- elastic properties

Both the troponin and tropomyosin, and the myosin isoforms contribute to resistance to fatigue.

Question 10

List the differences between Type I and Type II muscle fibres.

Answer 10

As a result of myofibril and protein isoform variations, muscle fibres can be broadly split into groups based on their contractile properties (fast and slow twitch).

TYPE I (slow fibres) e.g. back extensor muscle:

• virtually inexhaustible
• high mitochondria (aerobic metabolism)
• oxidative phosphorylation
• extensive blood supply and abundant myoglobin

TYPE II (fast fibres):

• fatigue easily
• few mitochondria (anaerobic metabolism)
• glyoclytic
• poor vascularisation and lack myoglobin

Question 11

List some effects of training specific muscle fibre types.

Answer 11

Untrained individuals have a 1:1 ratio of fast (IIA and IIX) to slow (I) twitch fibres.

• long and middle distant runner have about 60-70% slow twitch
• sprinters have about 80% fast twitch
• trainees for sports that require the greatest aerobic and endurance capacities have slow muscle up to 90-95%
• trainees for sports that require greater anaerobic capacities (strength and power) have fast muscle around 60-80%

Question 12

How would a marathon runner’s muscles be adapted to their sport?

Answer 12

1. Muscles are small but fatigue-resistant
2. Muscles are dense and strong for their size, with a high oxidative capacity of the muscles
3. They can work over very long periods of time
4. They don’t contain explosive strength

Question 13

How would a sprinter’s muscles be adapted to their sport?

Answer 13

1. Muscles produce rapid, powerful contractions
2. Muscles are easily fatigued at maximum effort
3. Muscles have a low oxidative capacity via mitochondria
4. Muscle can exert a high force per cross-sectional area of muscle

Question 14

How would a power lifter’s muscles be adapted to their sport?

Answer 14

1. Muscles are hypertrophied
2. They are highly glycolytic
3. They fatigue easily
4. Have a high muscle to total body mass ratio
5. Muscle size begins to interfere with locomotion

Thus, the power lifter is moving along the same path of adaptation as the sprinter, but more extreme.
Their power to weight ratio is moving to a point where they are less able to move their body through a distance, and hence would be less fast at running.

Question 15

Describe the gender differences in skeletal muscle.

Answer 15

There are over 3000 genes that are different between male and female skeletal muscle.

Differences in myosin isoforms.
TYPE I (slow):
M - 36%, female - 44%

TYPE IIA (fast):
M - 41%, F - 34%

Males have a larger fibre cross-sectional areas (CSAs).

Men have more fast twitch muscle in general.

Question 16

Describe testosterone, and how it contributes to muscles.

Answer 16

Testosterone is a primary male sex hormone required for the development of the male reproductive system. It also promotes secondary sexual characteristics, such as body hair, development of a deep voice, and increased muscle and bone mass.

Testosterone is a natural anabolic-androgenic-steroid (AAS).
It promotes the commitment of mesenchymal pluripotent cells into myogenic lineage, and inhibit adipogenesis (via an androgen receptor-mediate pathway).

It also stimulates:

• satellite cell replication
• muscle protein synthesis
• fibre hypertrophy

Question 17

What are some of the adverse effects of using synthetic anabolic steroids and some of their uses in treatments?

Answer 17

Using anabolic steroids can lead to the development of irreversible adverse effects.

• stimulate the development of male sexual characteristics in females (e.g. deep voice, sex organs, hair growth)
• increase RBC production
• acne
• oily skin
• hair loss
• liver disease
• heart disease
• mood swings, irritability and aggression
• depression
• cholestrol altered
• high BP
• suicidal tendencies
• weight loss
• testicles can shrink
• menstrual irregularity

Treatments:

• delayed puberty
• hypogonadism
• impotence in men
• breast cancer
• endometriosis

Question 18

Describe the pax genes and regeneration.

Answer 18

The satellite cells can be identified by the paired/homeodomain transcription factors Pax3 and Pax7.

Pax3 establishes MuSCs identity during embryonic development , expressed in the presomitic mesoderm, required for survival of the ventro-lateral dermomyotome, which gives rise to the hypaxial and limb musculature.

Pax7 establishes MuSCs during late foetal and perinatal growth.

Pax7 null mice are deficient in the number of MuSCs and fail to regenerate muscle after injury in adult mice.

Pax 3 and 7 are required for MuSC formation and regeneration

Question 19

How does muscle repair differ with the type of injury?

Answer 19

In the case of a minor injury, we get the recruitment of satellite cells to the muscle fibre. The damaged muscle fibre necroses, and there is an inflammatory response. Macrophages and neutrophils will respond to the inflammation. There is an increase in satellite cell proliferation, which fuse with the muscle fibre and regenerate it.
Thus, this injury is reversible.

Minor cases:
Damage induces fibre break –> recruitment of satellite cells –> accumulate at intact side of fibre –> proliferate and fuse to repair muscle fibre –> self renewal

In the case of more severe injury, there is incomplete regeneration of muscle fibre, and so fibrotic tissue forms.

Severe case:
satellite cells proliferate and align on the extracellular matrix. During homeostasis the satellite cells are quiescent, they express Pax 3, Pax 7, MyF5 and NOTCH. Upon damage they rapidly upregulate MyoD, MyF5 and Pax 7. Following amplification the myoblasts express the differentiating genes myogenin and MyoD. They then align at the extracellular matrix.

Question 20

What are the main phases of regeneration?

Answer 20

3 main phases:

1) Degeneration/inflammation phase: (first few days)
- Myofibre rupture and necrosis, formation of hematoma, inflammatory response
- inflammation involves neutrophils and macrophages.
- M1: pro-inflammatory
- M2: anti-inflammatory, satellite cell activation

2) Regeneration Phase: 4-5 days pi.
- Phagocytosis of damaged tissue, satellite cell activation and proliferation.
- Regenerated myofibres with centrally located myonuclei.

3) Remodeling phase: 2/3 wks
- maturation of regenerated myofibers, restoration of blood supply and innervation, recovery of muscle functional capacity and also fibrosis and scar tissue formation.
- TGF-B1 at lesion site improves muscle fibre.

There is then the complete or partial muscle maturation/functional repair.

• Extracellular matric (ECM) deposition, scar tissue formation.
• Innervation of regenerated myofibres.

Question 21

Describe sarcopenia.

Answer 21

Sarcopenia is the age-related loss of muscle mass (muscle ageing). There is a 3-8% decrease per decade after the age of 30, and gets higher after the age of 60.

It has an impact on the elderly; they are more prone to injury and disability from falls, etc.
It’s associated with decreased satellite cells number and recruitment.

There are biochemical and metabolic changes:

• mitochondrial mutations
• reduced oxidative and glycolytic enzyme activity
• reduced endocrine functions
• reduced physical activity

Question 22

How does testosterone help in treating muscle disease?

Answer 22

It can help elderly patients who have lost muscle mass due to age.
It can also be used to alleviate muscle loss in muscle-wasting diseases.

However, it can run the risk of worsening osteoporosis.

Question 23

Glossary

Answer 23

Myoblasts – a cell commitment to a myogenic lineage, but not yet differentiated.
Myogenic Regulatory Factors – Transcription factor required for commitment and terminal differentiation of muscle cells.
Satellite cells - divide and serve as a source of new myonuclei during postnatal growth. They contribute to the growth of the fibres and participate in the regeneration process.
Slow muscle - produce slow maintained contractions that are virtually inexhaustible.
Fast muscle - generates high force contractions that fatigue easily.
Muscle Hypertrophy - increase in muscle mass due to increase in fibre size
Muscle Hyperplasia – increase in the number of muscle fibres.
Sarcopenia - age-related loss of muscle mass
Fibrosis -
is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of permanent scar tissue.

Satellite cells (MuSCs) are fundamental for repair, regeneration and maintenance of muscle.